Objectives Using data from a large random sample of U.S. older adults (N = 7982), the effect of loneliness and social isolation on all-cause mortality was examined considering their separate and combined effects. Methods The UCLA-3 Loneliness Scale and the Social Network Index (SNI) were used to define loneliness and social isolation. Cox proportional hazards regression models were performed. Results Among study participants, there were 548 deaths. In separate, adjusted models, loneliness (severe and moderate) and social isolation (limited and moderate social network) were both associated with all-cause mortality. When modeled together, social isolation (limited and moderate social network) along with severe loneliness remained significantly associated with mortality. Discussion Results demonstrate that both loneliness and social isolation contribute to greater risk of mortality within our population of older adults. As the COVID-19 pandemic continues, loneliness and social isolation should be targeted safely in efforts to reduce mortality risk among older adults.